| Gene/Disease Pair: | BRAF : cardiofaciocutaneous syndrome |
| HGNC:1097 | MONDO_0015280 | |
| Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
| Expert Panel: | RASopathy EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 5 |
|
Genetic Evidence
|
Case-Level Data
|
Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Total | Counted | ||||||||
|
Variant Evidence
|
Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
16
|
12 |
Niihori T et al. 2006 Mar (PMID:16474404); Rodriguez-Viciana P et al. 2006 Mar 3 (PMID:16439621);
|
||||
| Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | |||||||||
| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
|
||||||||
| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
|
|||||||
| Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | ||||||||||
| Segregation Evidence | Evidence of segregation in one or more families | Sequencing Method | 0-3 | 3 |
|
|||||||
| Total LOD Score | Canditate Gene Sequencing | Exome/Genome or all genes sequenced in linkage region | ||||||||||
| 2-2.99 | 0.5 | 1 | ||||||||||
| 3-4.99 | 1 | 2 | ||||||||||
| ≥5 | 1.5 | 3 | ||||||||||
|
Case-Control Data
|
Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Points | PMIDs/Notes | |||||||
| Points/Study | Max | Total | Counted | |||||||||
| Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 |
|
||||||||
| Aggregate Variant Analysis | 0-6 |
|
||||||||||
| Total Genetic Evidence Points (Maximum 12) | 12 |
|
||||||||||
|
Experimental Evidence
|
Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | |||||||
| Default | Range | Max | Total | Counted | ||||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
|
0.5 | ||||||
| Protein Interaction | 0.5 | 0 - 2 | 0.5 |
Rauen KA et al. 2013 July 15 (PMID:23875798);
|
||||||||
| Expression | 0.5 | 0 - 2 | ||||||||||
| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
0
|
0 |
Han KM et al. 2015 May (PMID:25639853);
|
|||||
| Non-patient cells | 0.5 | 0 - 1 | 0 |
Rodriguez-Viciana P et al. 2006 Mar 3 (PMID:16439621); Rauen KA et al. 2013 July 15 (PMID:23875798); Wen C et al. 2013 Nov 14 (PMID:24409384);
|
||||||||
| Models | Non-human model organism | 2 | 0 - 4 | 4 | 1 | 1 |
Anastasaki C et al. 2009 Jul 15 (PMID:19376813); Moriya M et al. 2015 Dec 20 (PMID:26472072);
|
|||||
| Cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
|
||||||||
| Rescue in non-human model organism | 2 | 0 - 4 | ||||||||||
| Rescue in cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue in patient cells | 1 | 0 - 2 | ||||||||||
| Total Experimental Evidence Points (Maximum 6) | 1.5 |
|
||||||||||
| Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence
(0-6 points) |
Total Points
(0-18) |
Replication Over Time (Y/N) | ||
| Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental
Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
| Assigned Points | 12 | 1.5 | 13.5 | YES | ||
| CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
| MODERATE | 7-11 | |||||
| STRONG | 12-18 | |||||
| DEFINITIVE | 12-18 AND replication over time | |||||
| Valid contradictory evidence (Y/N)*
|
|
|||||
| CALCULATED CLASSIFICATION (DATE) |
Definitive
07/24/2018
|
|||||
| EXPERT CURATION (DATE) |
Definitive
07/24/2018
| |||||
| EVIDENCE SUMMARY |
There is a definitive association between alteration of the BRAF gene and a CFC phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in BRAF in patients with CFC syndrome (Gripp et al., 2007; Louati et al., 2014; Makita et al., 2007; Mucciolo, Dello Russo, D'Emidio, Mesoraca, & Giorlandino, 2016; Narumi et al., 2007; Niihori et al., 2006; Rodriguez-Viciana, Tetsu, et al., 2006). The BRAF gene is located in the Ras/MAPK pathway which is associated with the Noonan phenotype and variants found in CFC patients in this gene disrupt the RAS pathway function as demonstrated by both mouse and zebrafish models (Anastasaki, Estep, Marais, Rauen, & Patton, 2009; Aoki et al., 2016; Moriya et al., 2015; Rauen, 2013).
|
|||||